At the present time, approximately 85% of all blood coagulation testing is carried out in the laboratory by means of a widely discredited and time-consuming procedure. An urgent need therefore exists for an instrument which is capable of measuring accurately and promptly the clotting time of blood at the patient's bedside or in the surgical suite. The value of a portable device of this kind relates primarily to surgical procedures which require the administration of Heparin. Immediate, accurate and reliable measurement of clotting time are essential to determination of the correct Heparin dosage in order to prevent possibly fatal hemorrhage or thrombosis. Such a portable automatic instrument, which can be operated by a nurse, without the intervention of a doctor or laboratory technician, will therefore satisfy an important unmet need in current medical practice.
Prior art instruments for determining the process of blood coagulation almost without exception have been based on the automation of established and well known manual test methods such as Lee White, and ACT (Activated Clotting Time). As such, they share the limitations of the manual methods (the ambiguity of the end point and the related variability of test to test results). Such variability is amplified by the interaction of the coagulating blood with the solid bodies which constitute an essential element of the automatic devices based on Lee White and ACT. All prior art patents reviewed hereinbelow, which are based on Lee White and ACT and various modifications thereof, employ intrusive solid elements which introduce, through their interaction with the blood, an undetermined variable to the mechanism of clotting. As a result, the end point recorded may vary significantly from the true end point.
The instrument described in U.S. Pat. No. 3,836,333, in common with similar other instruments, depends on mechanical impedance, and therefore is subject to test to test variability due to the effect of a foreign body. This effect is enhanced when a relatively large volume of plasma or whole blood is employed, for example, in excess of 50 microliters, and is demonstrated in procedures such as dialysis, cardiac bypass and open heart surgery which require the extra corporeal circulation of the blood. The contact with foreign materials inherent in these procedures requires the administration of heparin to prevent clotting of the blood which would otherwise occur. It must therefore be assumed that the clotting time measured by mechanical impedance instruments is shortened by an undetermined increment, for the same reason. Unlike the effect of exposure to a glass surface of fixed dimensions, which is constant, that of the intrusive elements in motion relative to the blood may be variable within limits that have not been determined. Variability is further increased by the use of activators such as diatomaceous earth or glass particles to shorten coagulation time. Such activators, by nature of their particle size variability contribute to further uncertainties in the measurement of true clotting time. The following U.S. Pat. Nos. 3,635,678; 3,695,842; 3,967,934; 4,081,242; 4,125,327; 4,388,823; 4,599,219 all fall within the category of deficiencies defined for U.S. Pat. No. 3,836,333.
Despite the universal need for portability in clotting time instruments, and the growing constraints on medical costs, the instruments described in the foregoing patents are of limited utility in medical practice due to their relatively large size, complexity and cost, in addition to their operating deficiencies. The same conclusion follows, a fortiori in respect to U.S. Pat. 4,014,650. Clot detection based on ultrasonic generation is prohibitively expensive, due to the relatively complex equipment used. U.S. Pat. Nos. 3,699,437 and 3,841,643 teach a method of detecting clot formation and determining clotting time by an analog recording of changes in electrical resistance. The reliability of this method is based on the implicit, but questionable assumption, that the point of minimum resistance coincides with clot formation. Blood is an aequeous medium containing electrolytes including calcium, sodium, potassium and phosphorus, among others. The concentration of these ions will vary depending on the medical condition of the patient. Calcium deficiency is a known characteristic in such conditions as rickets and tetany. In other disorders, sodium may be present in undesirably high concentration. Electrical resistance of an aequeous medium varies in proportion to the concentration of electrolytes. The passage of current through such a medium will also affect its composition. For all of these reasons the reliability of resistance instruments, in the absence of positive and simultaneous confirmation (such as that provided by the slide method as described hereinafter in experiment II) must be questioned.
U.S. Pat. No. 4,217,107 teaches an indirect method of detecting clot formation, VIZ. by differentiation of the changes in the amount of scattered light measured discontinuously. The moment of clot formation is derived by mathematical inference, based on the assumption that first clot formation coincides with the first indication that the slope of the curve so generated has changed from positive to negative. As in the above listed patents the inferred time of clot formation has not been established by positive and simultaneous confirmation as in experiment II.
A similar system using light scatter techniques is shown in U.S. Pat. No. 4,252,536 wherein the resulting analog signal is digitized.
The instrument described in U.S. Pat. No. 4,756,884 is designed to measure and record APTT (Activated Partial Thromboplastin Time). The device is deficient in two respects. Its results have been shown to correlate poorly with standard laboratory procedures and APTT itself is a widely discredited test.
A generally recognized deficiency of the APTT method is reported in a paper entitled "Laboratory Monitoring of Heparin"--American Journal of Clinical Pathologists; October 1981. "A large change in APTT may correspond to only a small change in the Heparin concentration and thus may not be an indication for altering the Heparin dose." Otherwise stated, the relationship of the values reported, to the doses administered, is exponential when it should be linear for reliable and safe control. A test used by 85% of physicians, ("Thrombosis News" January 1983) is therefore known to be unreliable.